The broad objective of this program is a study of the mechanisms controlling normal and abnormal cell differentiation and development. Some of the questions which will be posed, stated in general terms, include: the mechanism by which the information encoded in the genetic material of the cell is transmitted to the sites of protein synthesis; the factors controlling the rates and types of protein synthesized by cells during the course of differentiation and development; the factors controlling the process by which precursor cells with a given genetic complement can give rise to cells which differ in structure and function; the determination of irreversibility of differentiation; the relationship between the structure and function of such subcellular elements as the nucleolus, chromosomes, nuclear membrane, ribosomes, mitochondria, and stroma during the course of cellular differentiation and development. As a model for pursuing these problems emphasis will be placed on studies of differentiation and development of hematopoietic cells. A multidisciplined approach to these problems will include ultrastructural, biochemical, biophysical, genetic and clinical studies. Experiments are designed to investigate regulatory mechanisms of normal and abnormal hematopoietic cell differentiation in man, rabbit, and adult and fetal mice. Control of specific protein production in normal and abnormal cell development will be studied employing, as a model, formation of embryonic and adult hemoglobins in mouse fetal erythroid cells developing in yolk sac and liver. In man, emphasis will be placed on studies of hemoglobin synthesis in normal subjects, and patients with thalassemia, characterized by a genetically determined selective defect in globin chain formation and a severe hemolytic anemia, and patients with hemoglobinopathies e.g. hemoglobin S. and hemoglobin C.